Macrophages are important mediators of resistance to infection and rejection of tumors. Bacteria or tumor cells which can induce cAMP in macrophages are able to inhibit macrophage-mediated cytotoxicity. Paradoxically, cAMP induces differentiation in a monocyte-like cell line, U937. The molecular basis of these diverse effects of cAMP on macrophage function is not well understood. Cyclic AMP-mediated events in other cells are the result of cAMP-dependent phosphorylation and subsequent modification of the function of a specific protein. Studies of human monocyte differentiation have demonstrated the presence of cAMP-dependent protein kinase II in peripheral blood monocytes and the subsequent induction of cAMP-dependent protein I during in vitro differentiation. This induction of PK I is not seen in human monocytic leukemia cells cultured in vitro, but human alveolar macrophages do possess both PK I and PK II. Further experiments will identify the specific substrates for PK I and PK II in macrophages. The role of these specific proteins in macrophage tumor cell cytotoxicity and in monocyte differentiation will then be examined. These studies will provide a greater understanding of macrophage function with clinical relevance for resistance to infections and for immunotherapy of malignant disease.